title: Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis.
abstract: BACKGROUND
  Glioblastoma (GBM) genomes feature recurrent genetic alterations that dysregulate core intracellular signaling pathways, including the G1/S cell cycle checkpoint and the MAPK and PI3K effector arms of receptor tyrosine kinase (RTK) signaling. Elucidation of the phenotypic consequences of activated RTK effectors is required for the design of effective therapeutic and diagnostic strategies.
  
  
  METHODS
  Genetically defined, G1/S checkpoint-defective cortical murine astrocytes with constitutively active Kras and/or Pten deletion mutations were used to systematically investigate the individual and combined roles of these 2 RTK signaling effectors in phenotypic hallmarks of glioblastoma pathogenesis, including growth, migration, and invasion in vitro. A novel syngeneic orthotopic allograft model system was used to examine in vivo tumorigenesis.
  
  
  RESULTS
  Constitutively active Kras and/or Pten deletion mutations activated both MAPK and PI3K signaling. Their combination led to maximal growth, migration, and invasion of G1/S-defective astrocytes in vitro and produced progenitor-like transcriptomal profiles that mimic human proneural GBM. Activation of both RTK effector arms was required for in vivo tumorigenesis and produced highly invasive, proneural-like GBM.
  
  
  CONCLUSIONS
  These results suggest that cortical astrocytes can be transformed into GBM and that combined dysregulation of MAPK and PI3K signaling revert G1/S-defective astrocytes to a primitive gene expression state. This genetically-defined, immunocompetent model of proneural GBM will be useful for preclinical development of MAPK/PI3K-targeted, subtype-specific therapies.
authors.affiliation: Corresponding Author: C. Ryan Miller, MD, PhD, University of North Carolina School of Medicine, 6109B Neurosciences Research Building, Campus Box 7250, Chapel Hill, NC 27599-7250. rmiller@med.unc.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Vitucci
authors.forename: Natalie O
authors.initials: NO
authors.lastname: Karpinich
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Bash
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Werneke
authors.forename: Ralf S
authors.initials: RS
authors.lastname: Schmid
authors.forename: Kristen K
authors.initials: KK
authors.lastname: White
authors.forename: Robert S
authors.initials: RS
authors.lastname: McNeill
authors.forename: Byron
authors.initials: B
authors.lastname: Huff
authors.forename: Sophie
authors.initials: S
authors.lastname: Wang
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras); C487757:Pten protein, mouse; C495971:Hras protein, mouse
keywords: Pten; astrocytes; genetically engineered mouse; glioblastoma; invasion